Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome.

Neonates with Down syndrome (DS) have a propensity to develop the unique myeloproliferative disorder, transient abnormal myelopoiesis (TAM). TAM usually resolves spontaneously in ≤3 months, but approximately 10% of patients with TAM die from hepatic or multi-organ failure. After remission, 20% of patients with TAM develop acute myeloid leukemia associated with Down syndrome (ML-DS). Blasts in both TAM and ML-DS have trisomy 21 and GATA binding protein 1 (GATA1) mutations. Recent studies have shown that infants with DS and no clinical signs of TAM or increases in peripheral blood blasts can have minor clones carrying GATA1 mutations, referred to as silent TAM. Low-dose cytarabine can improve the outcomes of patients with TAM and high white blood cell count. A number of studies using fetal liver cells, mouse models, or induced pluripotent stem cells have elucidated the roles of trisomy 21 and GATA1 mutations in the development of TAM. Next-generation sequencing of TAM and ML-DS patient samples identified additional mutations in genes involved in epigenetic regulation. Xenograft models of TAM demonstrate the genetic heterogeneity of TAM blasts and mimic the process of clonal selection and expansion of TAM clones that leads to ML-DS. DNA methylation analysis suggests that epigenetic dysregulation may be involved in the progression from TAM to ML-DS. Unraveling the mechanisms underlying leukemogenesis and identification of factors that predict progression to leukemia could assist in development of strategies to prevent progression to ML-DS. Investigation of TAM, a unique pre-leukemic condition, will continue to strongly influence basic and clinical research into the development of hematological malignancies.